The Cooperative Family Registry for Colorectal Cancer Studies (Colon CFR) is an NCI-supported consortium dedicated to the establishment of a comprehensive collaborative infrastructure for interdisciplinary studies in the genetics and genetic epidemiology of colorectal cancer. The cooperating institutions are collecting epidemiological information and laboratory specimens from families who represent the continuum of risk for colorectal cancer. A major area of etiological research to which the Colon CFR is committed is candidate gene association studies, where we plan to target selected "pathways", rather than focusing on isolated genes. This application, along with a parallel application submitted by Dr. John Potter, is meant to initiate the Colon CFR research on candidate genes. The Colon CFR has identified three pathways with which to start: folate metabolism and vitamin D/calcium, which are addressed in this application, and the NSAID pathway, which is addressed in Dr. Potter's application. For this application, we have the following specific aims: Folate. Conduct a family-based case-control association study of selected genes that are involved in the metabolism of folate. Our current list of genes of interest includes: serine hydroxymethyltransferase (SHMT1), mehylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), thymidylate synthase (TYMS or TS), S-adenosylhomocysteine hydrolase (AHCY or SAHH), ADA (adenosine deaminase), methionine adenosyl transferase 2A (MAT2A), folate receptor (FOLR1), reduced folate carrier (RFC1 or SLC19A1), S-adenosylmethionine decarboxylase (AMD1), gastric instrinsic factor (GIF), transcobalamin II (TCII), intrinsic factor cobalamin receptor (IFCR), and alcohol dehydrogenase 3 (ADH3). Vitamin D and Calcium. Conduct a family-based case-control association study of selected genes that are involved in the metabolism of vitamin D and calcium. Our current list of genes includes: vitamin D receptor (VDR), retinoid X receptor (RXR), vitamin D binding protein (DBF), calcium sensing receptor (CaSR), and the ileal sodium-dependent bile acid transporter (SLC10A2). Genotyping will primarily involve SNP-based haplotypes. For both pathways, analyses of gene-gene and gene-environment interactions will be included as appropriate.